Aberrant growth control in neoplastic epithelia is frequently associated with alterations in the expression or function of growth factors and their cognate receptors. Expression of insulin-like growth factors (IGFs) is up-regulated in various neoplastic cell types, suggesting that an autocrine loop involving these growth factors and their receptor, the IGF-I receptor (IGF-IR), contributes to the tumor cell phenotype. In vivo, targeted disruption of the Igf-Ir gene results in severe embryonic growth retardation and perinatal mortality. Moreover, the skin of IGF-IR null mice is hypoplastic and contains fewer hair follicles than that of control littermates, indicating that IGF-IR function is essential for normal embryonic development of the epidermis and its appendages. Remarkably, embryonic fibroblast cell lines derived from IGF-IR null mice are uniquely resistant to transformation by a variety of oncogenes. This defect can be overcome by re-introduction of a functional IGF-IR, indicating that this signaling pathway is obligatory for fibroblast transformation. Although the great majority of human tumors arise in epithelia, analogous studies have not been performed in any epithelial cell type. We have established epidermal cell lines by introducing the v-ras-Ha oncogene into primary keratinocytes from IGF-IR null mice and control littermates. Both sets of cell lines give rise to squamous tumors when grafted onto the backs of nude mice, arguing against an obligatory role for IGF-IR in v-ras-Ha-mediated epidermal tumorigenesis. We will be assessing the involvement of IGF-IR in epidermal neoplasia mediated by other oncogenes, and in additional studies, will examine the requirement for IGF-IR in the regulation of normal skin function following transplantation of IGF-IR null skin onto nude mouse hosts.